7L5D

The crystal structure of SARS-CoV-2 Main Protease in complex with demethylated analog of masitinib

7L5D の概要

• エントリーDOI: 10.2210/pdb7l5d/pdb
• 分子名称: 3C-like proteinase, N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)-4-[(piperazin-1-yl)methyl]benzamide, DIMETHYL SULFOXIDE, ... (5 entities in total)
• 機能のキーワード: sars-cov-2, covid-19, 3cl, main protease, masitinib, demethylation, analog, structural genomics, center for structural genomics of infectious diseases, csgid, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34991.07

構造登録者

Tan, K.,Maltseva, N.I.,Jedrzejczak, R.P.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (登録日: 2020-12-21, 公開日: 2020-12-30, 最終更新日: 2023-10-18)

主引用文献

Drayman, N.,DeMarco, J.K.,Jones, K.A.,Azizi, S.A.,Froggatt, H.M.,Tan, K.,Maltseva, N.I.,Chen, S.,Nicolaescu, V.,Dvorkin, S.,Furlong, K.,Kathayat, R.S.,Firpo, M.R.,Mastrodomenico, V.,Bruce, E.A.,Schmidt, M.M.,Jedrzejczak, R.,Munoz-Alia, M.A.,Schuster, B.,Nair, V.,Han, K.Y.,O'Brien, A.,Tomatsidou, A.,Meyer, B.,Vignuzzi, M.,Missiakas, D.,Botten, J.W.,Brooke, C.B.,Lee, H.,Baker, S.C.,Mounce, B.C.,Heaton, N.S.,Severson, W.E.,Palmer, K.E.,Dickinson, B.C.,Joachimiak, A.,Randall, G.,Tay, S.
Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.
Science, 373:931-936, 2021

PubMed Abstract: There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern (B.1.1.7, B.1.351, and P.1).

PubMed: 34285133
DOI: 10.1126/science.abg5827

実験手法

X-RAY DIFFRACTION (1.58 Å)